Earlier we showed altered expression of Hsp40s, nucleotide exchange factors (NEFs) and several TPR-domain proteins affect prion propagation in wild type and Hsp70 mutant cells. We also identified several Hsp40 and TPR protein mutant alleles that impair or enhance prion propagation. Together our data imply that many, if not all the observed effects of co-chaperones on prions are mediated by their regulation of Hsp70 activities. In many instances the same conditions producing a significant effect on one prion have little or no effect on a different prion, pointing to a prion preference or specificity of the Hsp70/co-chaperone pairings. Targeting the two major yeast Hsp40s (Ydj1p and Sis1p) , we have identified mutations that alter prion propagation in both positive and negative ways. Characterization of these mutants is ongoing. Overexpression of Ydj1p was shown by others to "cure" cells of the URE3 prion. Biochemical analysis of interactions of Ydj1p with soluble and amyloid forms of Ure2p (the protein determinant of URE3) led another group to conclude that this curing was due to Ydj1p binding to Ure2p and preventing its incorporation into amyloid. Our recent work showed that the only domain of Ydj1p required for eliminating URE3 was its Hsp70-regulating J-domain, which showed that curing was indirect and required Hsp40/Hsp70 interaction. Although other Hsp40s do not cure URE3, we showed that the J-domain of Sis1p could cure URE3 when separated from the remainder of the protein, highlighting the specific aspect of Hsp70 regulation in the curing and the functional redundancy of Hsp40 domains. We went on to show that curing efficiency depended on the particular isoform of Hsp70 and that Hsp70s from another species could also mediate the curing, again at different efficiencies. This work identifies specific Hsp40/Hsp70 pairings that influence prion propagation in defined ways, and shows evolutionary conservation of very subtle functional distinctions among Hsp70s.